The overall goal of the research is to achieve a deeper understanding of in vivo nitrogen metabolism in patients with urea cycle defects and of differences in the bioavailability of enteral vs. systemic sources of nitrogen. We, and others, have argued that stable isotopic investigations of nitrogen metabolism provide the most generally applicable approach to the assessment of the underlying metabolic state of urea cycle patients, particularly those who have partial enzymatic deficiencies (e.g. heterozygous carriers of ornithine transcarbamylase deficiency; OTCD). Our preliminary studies (described below) have led us to conclude that OTCD carriers and mildly affected hemizygous OTCD males have a specific compromise in their ability to transfer the amide-N group of glutamine to urea. In these studies the OTCD carriers had near normal absolute rates of urea synthesis at protein intakes less than 0.8 g/kg/d, and sources of urea nitrogen other than glutamine appear to be of greater quantitative importance to these individuals than they are to normal subjects. The results have led us to the following hypotheses: 1: Urea precursors derived from the first-pass intestinal metabolism of dietary protein are utilized more efficiently for ureagenesis than are precursors derived from tissue metabolism. 2: As a consequence, individuals who have a compromised urea cycle activity are able to metabolize excessive dietary protein more effectively than peripherally generated precursors. This underlies the observation that the imposition of stress or infection is often associated with metabolic decompensation in symptomatic OTCD. 3: The difference in the efficiency with which urea is synthesized from substrates of intestinal and peripheral origin is an important factor in the variable phenotype and episodic nature of OTCD.